Fractional Hepatic Insulin Extraction Research Articles

134-OR: Comparison of Glucose-Insulin Homeostasis in People with Postprandial Hypoglycemia after Gastric Bypass Surgery and Nadir Plasma Glucose <50 mg/dl vs. >50 mg/dl

Background: Mechanisms of postprandial hypoglycemia following gastric bypass (GB) surgery (PBH), remain incompletely understood. Thus, we aimed to assess the role of insulin secretion/beta-cell function (BCF), fractional hepatic insulin extraction (HE), insulin sensitivity (SI) and rate of glucose appearance (Ra) in patients with biochemically moderate and severe hypoglycemia. Methods: A total of 23 subjects with PBH (mean±SD age 41±12 years, BMI 28.1±6.1 kg/m2, 6.0±2.5 years since GB surgery) underwent an oral glucose tolerance test (75g of glucose), with frequent blood sampling for determination of glucose, insulin and C-peptide concentrations for up to 180minutes. Indices of BCF, HE, SI and Ra were calculated using the oral minimal model method and compared between subjects with nadir plasma glucose during the test below (severe hypo) and above 50mg/dL (moderate hypo). Results: Mean±SD nadir glucose was 43.3±6.0mg/dL in the severe hypo group and 60.1±9.1mg/dL in the moderate hypo group. Differences between the groups were found for indices of BCF, HE and Ra, whereas no significant differences were observed for SI (Figure 1). Conclusion: Present findings confirm three candidate mechanisms involved in PBH: increased BCF, diminished HE and faster Ra. Disclosure D. Herzig: None. M. Schiavon: None. A. Tripyla: None. V. Lehmann: None. J. Meier: None. S. Jainandunsing: None. C. Dalla man: Research Support; Self; Becton, Dickinson and Company, Sanofi-Aventis Deutschland GmbH. L. Bally: None. Funding Swiss National Science Foundation (PCEGP3_186978); Italian Ministry of Education, University and Research (Law 232/2016); University of Padova; Diabetes Center Berne

Dissection of hepatic versus extra-hepatic insulin clearance: Ethnic differences in childhood.

Adult African American (AA) women have one third of the hepatic insulin clearance of European American (EA) women. This lower hepatic (but not extra-hepatic) insulin clearance in AA individuals is associated with higher plasma insulin concentrations. This study aims to understand whether impairment of hepatic insulin clearance is seen in AA individuals since childhood, possibly suggesting that genetic/epigenetic factors, rather than lifestyle only, contribute to this. A total of 203 children (105 male and 98 female (55 AA, 88 EA and 60 Hispanic American [HA]; ages, 7-13 years; mean BMI, 19 kg/m2 )) underwent the frequently applied intravenous glucose tolerance test (FSIGT) at the University of Alabama at Birmingham, General Clinical Research Center and Department of Nutrition Sciences. Glucose, insulin and C-peptide levels were measured and hepatic and extra-hepatic insulin clearances were calculated using mathematical modelling. Fractional hepatic insulin extraction (FEL ) was lower in AA than in EA children (mean (SD), 19% (20%) vs 33% (20%); P = 0.0007). Adjusting for age, Tanner stage and body fat, FEL was lower in AA than in EA children (P = 0.0012), and there was a slight sex-related difference (FEL, 24% (10%) vs 29% (10%) in boys vs girls; P = 0.04). Extra-hepatic insulin clearance did not differ with ethnicity (27 (12), 21 (12) and 24 (28) mL/kg/min for AA, HA and EA children, respectively; P > 0.05). At a young age, FEL is lower in AAs than in EAs, which does not rule out genetic/epigenetic factors. These differences are related to hyperinsulinaemia and, over time, could possibly contribute to metabolic disorders in AA individuals.

Metabolic Differences among Children of Different Ethnicities Are Magnified when Hepatic Insulin Extraction Is Included

Disposition index (DI) combines insulin sensitivity (SI) and beta-cell function (acute insulin response AIRg), and is a predictor of type 2 diabetes (T2DM). Insulin clearance, an important factor in glucose metabolism, is not included, yet can vary among ethnic groups. Our aim is to examine the differences among the DI in different ethnicities, and group subjects considering not only SI and AIRg, but also fractional hepatic insulin extraction (FEL). We used data from 203 normal glucose tolerant children that underwent FSIGT [55 African American (AA), 88 European American (EA), 60 Hispanic American (HA), ages 7-13 years, mean BMI = 19 kg/m2, basal glucose = 99 mg/dL, insulin = 78 pM, C-peptide = 511 pM]. Recent studies proved that HA and AA adults have an increased risk of developing T2DM. However, such studies are of interest for children of different ethnicities. The three DI hyperbolas, associated with ethnic groups (Figure 1A), are similar to each other. In contrast, cluster analysis also including FEL (Figure 1B), reveals that in these children 3 different clusters exist, (silouhette values > 0.6 in 63% of subjects in cluster 1, 87% in cluster 2, and 95% in cluster 3), and they do not necessarily coincide with ethnicity. Thus, FEL differs among children and it needs to be considered, together with SI and AIRg, in order to clarify diabetes risk among children of different ethnicities. Disclosure F. Piccinini: None. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.

Modeling the oral glucose tolerance test in normal and impaired glucose tolerant states: a population approach

Objective: The conventional approach to analyzing data from oral glucose tolerance testing (OGTT) requires model identification in each individual separately (standard two stage, STS), ignoring knowledge about the population as a whole. In practice, however, the OGTT is sparsely sampled and individual estimates are often not resolvable from available data. This weakness is often encountered in large scale trials or epidemiological studies, leading to either multiple imputations or simply much less data available for analysis.Methods: We have applied a population approach, nonlinear mixed effects modeling, to plasma glucose, insulin and C-peptide data obtained from a 120 minute OGTT undertaken by 106 subjects with varying glucose tolerance. This method provides estimates of population means, variances and covariances of model parameters and empirical Bayes estimates of individual parameter values, as well as measures of intra-individual (within-subject) and inter-individual (between-subject) variability. The recently developed oral glucose minimal model was used to evaluate insulin sensitivity, and a combined model approach was used to assess β-cell secretion.Results: Applying these models allowed for the reconstruction of insulin secretion and glucose absorption profiles and gave population indexes of insulin sensitivity (SI = 6.51 ± 1.20 × 10−4 min−1·μU−1·ml), fractional hepatic extraction of insulin (F = 0.522 ± 0.291) and fractional insulin clearance (kI = 0.258 ± 0.151 min−1). Whereas the traditional approach to parameter estimation failed to recover estimates in more than one third of the population, the population approach provided individual estimates in all subjects. Examination of the empirical Bayes estimates showed that individual parameter estimates were able to differentiate well between individuals at glucose tolerant states ranging from euglycemia to overt type 2 diabetes.Conclusions: Our findings suggest that population analysis is a powerful tool for obtaining accurate assessments of indexes of insulin sensitivity and β-cell function from the OGTT, especially in epidemiological studies with large numbers of sparsely sampled subjects.

The Differential Effect of the Phytoestrogen Genistein on Cardiovascular Risk Factors in Postmenopausal Women: Relationship with the Metabolic Status

The wide family of the phytoestrogens has become an alternative to the classical hormonal therapy in menopause; nevertheless, some findings are still conflicting. To examine the effect of genistein administration on metabolic parameters and vascular reactivity considering the basal endocrine status of the patients. A randomized placebo controlled study was conducted at a university hospital. Fifty postmenopausal women participated. Thirty subjects (group A) were randomized to receive 54 mg/d genistein while 20 subjects (group B) were treated with the placebo for 24 wk. In group A, we distinguish two subgroups: 14 normoinsulinemic and 12 hyperinsulinemic patients. Anthropometric measures, hormonal and lipid assays, oral glucose tolerance test with glycemic, insulin, and C-peptide evaluation, indexes of insulin sensitivity and endothelial function, and euglycemic-hyperinsulinemic clamps were performed. The insulin basal values significantly decreased in group A, whereas the homeostasis model index of insulin sensitivity and the fasting glucose levels significantly improved compared with placebo group. The genistein administration decreased fasting glucose and area under the curve glucose levels in the normoinsulinemic patients after treatment. In the hyperinsulinemic patients, a significant reduction in fasting insulin, fasting C-peptide, and area under the curve insulin levels as well as an increase in fractional hepatic insulin extraction was shown. In these patients, high-density lipoprotein cholesterol levels were significantly improved. The endothelium-dependent and -independent dilatation improved in the treated group. Normoinsulinemic patients showed both a significantly enhanced flow-mediated and nitrate-mediated dilatation, whereas no significant changes were found in the hyperinsulinemic group. The glycoinsulinemic metabolism and the endothelial function were significantly influenced by genistein. In particular, normoinsulinemic patients showed an improvement in glycemic and vascular reactivity indexes. Conversely, an improvement in the insulin sensitivity indexes was noted in hyperinsulinemic patients.

L-Folic Acid Supplementation in Healthy Postmenopausal Women: Effect on Homocysteine and Glycolipid Metabolism

Hyperhomocysteinemia as well as alterations of glycemic and lipidic metabolism are recognized as risk factors for cardiovascular diseases. The aim of this study was to examine the effect of L-folic acid supplementation on homocysteine (Hcy) and related thiols, such as cysteine (Cys) and Cys-glycine (Cys-Glyc) pathways and their relationship to glucose, insulin, and lipidic metabolism in normoinsulinemic postmenopausal women. This study was a randomized placebo, not double-blind, trial. The study was performed in an academic research center. Twenty healthy postmenopausal women were selected. No patient was taking drugs known to affect lipid or glucose metabolism. Patients underwent two hospitalizations before and after 8 wk of L-acid folic (7.5 mg/d) or placebo administration. The glycemic metabolism was studied by an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Hcy metabolism was studied by a standardized oral methionine-loading test. Hcy, Cys, and Cys-Glyc, basally and after a methionine loading test, were measured. Basal insulin, glucose, and peptide C levels as well as area under the curve for insulin, area under the curve for peptide, hepatic insulin extraction, and metabolic index were assayed. The total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol levels and the cholesterol/HDL and LDL/HDL ratios were also measured. The total basal Hcy concentration and the plasma postmethionine loading Hcy values were significantly decreased (P < 0.01) in L-folic acid-treated patients, whereas postmethionine loading Cys-Glyc levels were markedly increased (P < 0.02). Furthermore, L-folic acid intake induced a significant improvement in carbohydrate metabolism through an increase in fractional hepatic insulin extraction (P < 0.05) and peripheral insulin sensitivity (P < 0.02) in normoinsulinemic women. HDL levels considerably increased, inducing an improvement in other atherosclerotic indexes, such as cholesterol/HDL and LDL/HDL ratios (P < 0.03). These results show that folic acid supplementation lowers plasma Hcy levels and improves insulin and lipid metabolism, reducing the risk of cardiovascular disease.

Naloxone decreases insulin secretion in hyperinsulinemic postmenopausal women and may positively affect hormone replacement therapy

Objective: To evaluate the influence of the opioid system on glyco-regulation in postmenopausal women before and after hormone replacement therapy (HRT). Design: Prospective nonrandomized clinical study. Setting: Academic research environment. Patient(s): Twenty-one healthy normo- or hyperinsulinemic postmenopausal women. Intervention(s): Oral glucose tolerance test (OGTT) (saline study), OGTT with IV injection of naloxone (naloxone study), and hyperinsulinemic euglycemic clamp performed before treatment, after 12 weeks of estrogen replacement therapy (ERT), and after 12 additional weeks of estro-progestin combined therapy (i.e., HRT). Main Outcome Measure(s): Glucose, insulin, and c-peptide plasma levels assessed in fasting condition and during the two OGTTs (area under the curve [AUC]). Evaluation of fractional hepatic insulin extraction (FHIE) and peripheral sensitivity to insulin. Result(s): At baseline, there is a greater increase of the FHIE and a more significant reduction of the insulin AUC in the hyperinsulinemic patients during the naloxone study compared with the saline study. In these women, ERT enhanced the c-peptide AUC and improved the FHIE; naloxone infusion mainly increased these two parameters. HRT did not induce any further change. Conclusion(s): Endogenous opioid peptides are involved in the modulation of carbohydrate metabolism in menopause in hyperinsulinemic patients more than in other patients. The favorable changes of the glyco-insulinemic metabolism induced by HRT may be partially due to the induction of the opioidergic activity.

Differential effect of transdermal estrogen plus progestagen replacement therapy on insulin metabolism in postmenopausal women: relation to their insulinemic secretion.

To evaluate the impact on glucose and insulin metabolism of transdermal estrogen patches before and after the addition of cyclic dydrogesterone in postmenopausal women. We studied 21 postmenopausal women seeking treatment for symptomatic menopause. All patients received transdermal 50 micrograms/day estradiol for 24 weeks. After 12 weeks of treatment, 10 mg/day dydrogesterone were added. During both regimens, insulin and C-peptide plasma concentrations were evaluated after an oral glucose tolerance test (OGTT); insulin sensitivity was evaluated by a hyperinsulinemic euglycemic clamp technique. Insulin and C-peptide response to OGTT were expressed as area under the curve (AUC) and as incremental AUC; insulin sensitivity was expressed as mg/kg body weight. Fractional hepatic insulin extraction (FHIE) was estimated by the difference between the incremental AUC of the C-peptide and insulin divided by the incremental AUC of the C-peptide. Plasma hormone and lipid concentrations were assessed at baseline and at 12 and 24 weeks of treatment. Nine patients proved to be hyperinsulinemic and 12 were normoinsulinemic. Transdermal estrogen treatment significantly decreased the insulin AUC (P < 0.05) and the insulin incremental AUC in hyperinsulinemic patients; addition of dydrogesterone further decreased both the AUC and incremental AUC of insulin. Estrogen alone and combined with dydrogesterone evoked a significant increase in C-peptide AUC in hyperinsulinemic (79.2%) and normoinsulinemic (113%) patients. The treatment increased the values for FHIE and insulin sensitivity in all patients (P < 0.04) and in the hyperinsulinemic group (P < 0.01), whereas it did not affect such parameters in normoinsulinemic patients. Transdermal estrogen substitution alone and combined with cyclical dydrogesterone may ameliorate hyperinsulinemia in a selected population of postmenopausal women.

Role of opioid tone in the pathophysiology of hyperinsulinemia and insulin resistance in polycystic ovarian disease

Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of polycystic ovarian disease (PCOD). On the other hand, being generally admitted that opioids may play a role in glycoregulation and that opioid tone is altered in PCOD, an involvement of the opioids in determining the hyperinsulinemia of PCOD patients could be suggested. The aim of this study was to evaluate the effect of a chronic opioid blockade on insulin metabolism and peripheral insulin sensitivity in PCOD hyperinsulinemic patients. Twenty-three women with PCOD were studied. An oral glucose tolerance test (OGTT) and a clamp study were performed at baseline (during the follicular phase) and after 6 weeks of naltrexone administration (50 mg/d orally). Based on the insulinemic response to the OGTT, 16 women were classified as hyperinsulinemic and seven as normoinsulinemic. Naltrexone treatment significantly reduced fasting ( P < .05) and area under the curve (AUC) ( P < .02) plasma insulin levels only in the hyperinsulinemic group. Moreover, hyperinsulinemic patients showed similar C-peptide incremental areas after naltrexone treatment, whereas in the same patients the fractional hepatic insulin extraction calculated from the incremental areas of insulin and C-peptide was found to be increased after chronic opioid blockade by naltrexone. For peripheral insulin sensitivity, the hyperinsulinemic group showed significantly lower ( P < .01) total-body glucose utilization (M) compared with the normoinsulinemic group. No change in the M value was found after treatment in both groups. These data suggest that the insulin sensitivity and hyperinsulinemia after an OGTT are two distinct deranged features of the insulin disorder of PCOD patients.

The entero-insular axis in polycystic ovarian syndrome.

We investigated the contributions made by the entero-insular axis, proinsulin and the fractional hepatic extraction of insulin to the hyperinsulinaemia characteristic of polycystic ovarian syndrome (PCOS). We measured plasma glucose, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (7-36 amide) (GLP-1(7-36) amide), immunoreactive insulin (IRI), intact proinsulin (IPI), and C-peptide concentrations during a 75 g oral glucose tolerance test in seven normal weight women with PCOS and eight healthy women. Women with PCOS had higher fasting (P = 0.05) and integrated (P < 0.01) IRI concentrations than controls. Fasting C-peptide levels were similar in both groups but integrated C-peptide (P < 0.05) concentrations were greater in PCOS subjects than controls. Fasting and integrated concentrations of glucose, GIP and GLP-1(7-36) amide were similar in subjects with PCOS and controls. Although fasting IPI concentrations were similar in both groups, integrated IPI concentrations were higher (P = 0.05) in patients with PCOS. Women with PCOS had similar fasting but higher (P < 0.05) integrated IRI:C-peptide molar ratios than controls. Fasting and integrated IPI:IRI molar ratios were similar in both groups. These results confirm that lean women with PCOS have peripheral hyperinsulinaemia. The mild fasting hyperinsulinaemia is due to increased pancreatic secretion, whereas the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and reduced fractional hepatic extraction of insulin. Hyperproinsulinaemia is modest and appropriate in PCOS, GIP and GLP-1(7-36) amide do not contribute to the stimulated hyperinsulinaemia in PCOS.

Endocrinology: Effect of opioid blockade on insulin metabolism in polycystic ovarian disease

A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.

Effect of growth hormone on hepatic glucose and insulin metabolism after oral glucose in conscious dogs.

This study examined the effect of growth hormone (GH) on hepatic glucose metabolism and on the fractional extraction of insulin and glucagon after oral glucose administration. GH treatment [canine GH (0.75 mg/day for 7 days)] significantly increased basal portal vein and hepatic artery flow (P < 0.01 compared with pre-GH treatment). After GH treatment and after oral glucose, glucose levels significantly exceeded those before GH at 100 and 120 min in arterial and portal vein plasma and 120 min in the hepatic vein. The net hepatic uptake of glucose was similar before and after GH treatment. The increment of net nonhepatic splanchnic insulin balance above basal was 131 +/- 31 mU.kg-1.3 h-1 before and 272 +/- 46 mU.kg-1.3 h-1 after GH treatment (P < 0.05). An increase in fractional hepatic extraction of insulin occurred before GH treatment and was significantly greater at 60 min. In summary, despite the increased insulin content after GH administration, there was no change in hepatic uptake of glucose, indicating that the liver was also the site of insulin resistance.

Short- and long-term gliclazide effects on pancreatic islet cell function and hepatic insulin extraction in non-insulin-dependent diabetes mellitus

Nine non-obese males with non-insulin-dependent diabetes mellitus (NIDDM) were evaluated before and after 3 and 12 months (6 patients) treatment with the second generation hypoglycemic sulfonylurea: gliclazide. They underwent an oral glucose tolerance test, intravenous glucose and arginine tests measuring plasma insulin and C-peptide responses. Pre-hepatic insulin production and insulin delivery to peripheral tissues were calculated by deconvolution techniques and hepatic extraction of insulin estimated. An improvement was observed in the β-cell function of the patients on gliclazide treatment: reduction of fasting plasma glucose associated with a progressive increase in C-peptide level but insulin levels decreased at 12 months, suggesting an increase in hepatic insulin extraction at this time. In the same way, while plasma glucose values after oral and i.v. glucose were greatly reduced at 3 and 12 months treatment, insulin did not change but C-peptide levels increased significantly at 12 month treatment. While the prehepatic insulin secretion rate increased progressively on gliclazide during all glucose challenges, the fractional hepatic insulin extraction fell after 3 and increased at 12 month treatment, with opposite changes in insulin delivered to peripheral tissues. Thus the insulinogenic effect of gliclazide could be masked during long-term administration by a concomitant effect of gliclazide which increases hepatic extraction of insulin. The maintenance of the responsiveness to the non-glucose secretagogue, arginine, as evaluated by the C-peptide levels, before and after correction of hyperglycemia, suggested improvement of β-cell sensitivity to glucose after sulfonylurea treatment. When plasma glucose levels during gliclazide therapy were matched by glucose infusion to the pretreatment fasting plasma glucose, the acute insulin and C-peptide responses to arginine were also increased again, indicating that the β-cells were resensitized to the potentiating effect of glucose after sulfonylurea. In conclusion, gliclazide treatment increases insulin secretion and alters hepatic insulin extraction. Because C-peptide kinetic studies were not performed, the derived data related to pancreatic insulin secretion and hepatic insulin extraction are tentative and should be accepted with caution.

Beta-adrenergic stimulation contributes to incretin effect in conscious dogs.

Oral glucose administration increases insulin secretion to a greater extent than peripheral glucose infusion (incretin effect). It also augments protal vein blood flow, hepatic uptake of glucose, and fractional hepatic extraction of insulin. The mechanisms for these various effects are not known but could involve both neurogenic stimuli and gut hormones. The present studies examined the effect of a non-nutrient drink, 1 g/kg body wt oral mannitol, on these parameters during an intravenous glucose infusion in conscious dogs. The dogs had chronically implanted Doppler flow probes on the portal vein and hepatic artery and catheters in the portal vein, hepatic vein, and femoral artery. After a 30-min control period, an infusion of atropine, propranolol, phentolamine, or propranolol and phentolamine was begun. Thirty minutes later, glucose (13 mg.kg-1.min-1) was then infused into a peripheral vein for 120 min with continuation of the atropine and adrenergic blockade. Water or mannitol (10% solution) was administered orally 50 min after the initiation of the glucose infusion. Mannitol, but not water, significantly enhanced the insulin response to intravenous glucose, as indicated by higher insulin concentrations in the portal vein as well as more rapid reduction of the plasma glucose. This incretin effect was significantly attenuated by infusion of propranolol but not by atropine or phentolamine. Mannitol did not increase portal vein blood flow or have any effect on the hepatic uptake of glucose or the fractional hepatic extraction of insulin. Thus absorption of nutrient is not necessary for the incretin effect but is for the increased portal vein blood flow and increased fractional extraction of insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the entero-insular axis in insulin secretion

The concept of an entero-insular axis has its origins in the 19th Century, after the observation that greater amounts of glucose could be given orally rather than intravenously without producing glycosuria. However, convincing evidence that the gut is able to modify the insulin response to an oral glucose load was produced by two groups of investigators in the 1960s, who showed that oral glucose is much more effective in raising circulating insulin levels than intravenous glucose given in amounts sufficient to produce similar degrees of hyperglycaemia [ 1, 21. The term ‘entero-insular axis’ embraces all those gut factors which contribute to enhanced insulin secretion after ingestion of a meal [3]. Gastrointestinal hormones, collectively termed ‘incretins’ [4], were regarded until recently as the major transmitters of messages from the gut to the pancreatic islets apart from absorbed substrates themselves and their metabolites. It is now apparent that the entero-insular axis possesses an important neural as well as an endocrine component. Both appear to work against the ‘set’ determined by the circulating glucose concentration. The endocrine arm of the enteroinsular axis is better characterized, although far from completely understood. The following focuses on this arm, its role in the regulation of insulin secretion and the possible pathophysiological significance of its modification by dietary changes. Investigators in the 1960s had assumed that higher circulating levels of insulin were synonymous with increased insulin secretion. This assumption has more recently been questioned as a result of comparing peripheral venous plasma insulin and C-peptide responses to oral and intravenous glucose. Observations [ 51 that the increased plasma insulin response to hyperglycaemia resulting from oral versus intravenous glucose was not accompanied by a comparable increase in plasma C-peptide, led to the conclusion that the higher plasma insulin levels seen after oral glucose were due to a decreased fractional hepatic extraction of insulin rather than increased insulin secretion. Further work, based on matching the degree of hyperglycaemia in arterialized rather than venous blood, which is more representative of the stimulus to insulin secretion at B-cell level, has shown that the incretin effect is mediated by both increased secretion and decreased clearance of insulin in normal human subjects [6]. Nevertheless, the observable effect of oral carbohydrate on peripheral insulin levels can be largely accounted for by augmented insulin secretion, particularly when large carbohydrate loads are taken orally [ 71. Many peptides have been isolated from intestinal and nervous tissue which have the ability to stimulate insulin

The reduction of peripheral insulin concentrations in obese subjects following a hypocaloric diet: reduced pancreatic secretion or increased hepatic extraction?

The fasting hyperinsulinaemia characteristic of obesity is due to pancreatic hypersecretion and is accompanied by a corresponding increase in plasma C-peptide concentrations. The exaggerated plasma insulin and C-peptide responses to oral glucose in obese subjects which is greater for insulin than C-peptide suggests that the stimulated hyperinsulinaemia is due to both pancreatic hypersecretion and decreased fractional hepatic extraction of insulin. In obese subjects fasting and stimulated insulin concentrations, but not those of C-peptide, are lower after 3 weeks of energy restriction than before it. This reduction in fasting and stimulated insulin levels is, therefore, due to an increase in the fractional extraction of insulin by the liver rather than to a reduction in pancreatic secretion as had previously been supposed.

Fasting and postabsorptive hepatic glucose and insulin metabolism in hyperthyroidism.

The effect of thyroid hormone excess on hepatic glucose balances and fractional hepatic extraction of insulin and glucagon was examined in six conscious dogs with catheters in the portal vein, hepatic vein, and femoral artery and Doppler flow probes on the portal vein and hepatic artery. An oral glucose tolerance test was performed before and after the animals were made hyperthyroid by intramuscular thyroxine administration (100 micrograms.kg-1.day-1) for 10 days. In the basal state and after oral glucose, insulin and glucagon levels in the three vessels and the basal fractional hepatic extraction of insulin and glucagon were not significantly modified by thyroid hormone. These results suggest that in short-term thyrotoxicosis insulin secretion is not impaired, and the rise in fasting plasma glucose and increased hepatic glucose production could reflect hepatic insulin resistance, increased availability of precursors for gluconeogenesis, or increased glycogenolysis. Hyperthyroidism significantly increased basal flows in the portal vein (14.7 +/- 0.6 vs. 12.9 +/- 0.5 ml.kg-1.min-1), the hepatic artery (4.8 +/- 0.3 vs. 3.9 +/- 0.2 ml.kg-1.min-1) and vein (19.6 +/- 0.7 vs. 16.9 +/- 0.4 ml.kg-1.min-1), the fasting plasma glucose concentration (104 +/- 3 vs. 92 +/- 2 mg/dl), and basal hepatic glucose output (2.1 +/- 0.2 vs. 1.5 +/- 0.2 mg.kg-1.min-1). It did not alter the nonhepatic splanchnic uptake of glucose, the percent of orally administered glucose that appeared in the portal vein (47 +/- 2 vs. 45 +/- 11%), the percent of hepatic uptake of glucose (59 +/- 11 vs. 74 +/- 22%), or the shape of the glucose tolerance test.

Fractional hepatic extraction of insulin in man: is it constant?

The present study was designed to compare insulin extraction by the liver following oral glucose administrations of different size, in order to evaluate insulin removal by the liver in relation to the insulin exposure, and to the amount of ingested glucose. Insulin secretion by the pancreas was estimated by the measurement of peripheral C-peptide levels, and insulin extraction by the liver by the analysis of peripheral C-peptide to insulin ratios and relations. Ten healthy subjects (5 males and 5 females), aged 16 to 66 yr, with normal bw, and without family history of diabetes mellitus were investigated by means of the administration, on alternate days, of 50 and 150 g oral glucose loads. After the 150 g oral glucose load plasma glucose levels were significantly higher than after the 50 g oral glucose administration: glucose incremental areas of 1.45 +/- 0.12 vs. 0.55 +/- 0.04 mmol/l X min, respectively (p less than 0.001). Similarly, insulin concentrations were significantly higher following 150 g than after 50 g glucose ingestion: insulin incremental areas of 0.52 +/- 0.09 vs. 0.20 +/- 0.04 nmol/l X min (p less than 0.001). Also C-peptide levels were higher after 150 vs. 50 g oral glucose load: C-peptide incremental areas of 1.85 +/- 0.41 vs. 0.64 +/- 0.13 nmol/l X min (p less than 0.01). C-peptide to insulin molar ratios were similar during the two glucose challenge, and averaged 5.25 +/- 0.42 vs. 5.08 +/- 0.50 after 50 and 150 g oral glucose loads, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dexamethasone on hepatic glucose and insulin metabolism after oral glucose in conscious dogs.

To examine whether hyperinsulinemia associated with glucocorticoid treatment results solely from hypersecretion of insulin or also involves altered fractional hepatic extraction, oral glucose (1 g/kg body wt) was administered to dogs with or without dexamethasone treatment (2 mg/d for 2 d). Dexamethasone significantly increased basal glucose and insulin concentrations in the portal vein, hepatic vein, and femoral artery, reduced basal fractional hepatic extraction of insulin from 43 +/- 4% to 22 +/- 4%, and, after oral glucose, increased retention by the liver of net glucose released into the portal system from 27 +/- 4% to 53 +/- 13%. Intraportal insulin infusion (1 and 2 mU/kg per min) after 7 d of dexamethasone treatment (2 mg/d) caused less suppression of endogenous glucose production, and less exogenous glucose was required to maintain an euglycemic clamp than in control animals. Dexamethasone treatment is associated with: decreased basal fractional hepatic insulin extraction contributing to hyperinsulinemia; and less suppression of endogenous glucose production and increase in peripheral uptake in response to insulin, but no reduction in net hepatic glucose uptake after oral glucose.

Effects of alpha and beta adrenergic blockade on hepatic glucose balance before and after oral glucose. Role of insulin and glucagon.

In conscious dogs, phentolamine infusion significantly increased fasting portal vein insulin, glucagon, and decreased net hepatic glucose output and plasma glucose. Propranolol significantly decreased portal vein insulin, portal flow, and increased hepatic glucose production and plasma glucose. Phentolamine, propranolol, and combined blockade reduced glucose absorption after oral glucose. alpha, beta, and combined blockade abolished the augmented fractional hepatic insulin extraction after oral glucose. Despite different absolute amounts of glucose absorbed and different amounts of insulin reaching the liver, the percent of the absorbed glucose retained by the liver was similar for control and with alpha- or beta blockade, but markedly decreased with combined blockade. Our conclusions are: (a) phentolamine and propranolol effects on basal hepatic glucose production may predominantly reflect their action on insulin and glucagon secretion; (b) after oral glucose, alpha- and beta-blockers separately or combined decrease glucose release into the portal system; (c) net hepatic glucose uptake is predominantly determined by hyperglycemia but can be modulated by insulin and glucagon; (d) direct correlation does not exist between hepatic delivery and uptake of insulin and net hepatic glucose uptake; (e) alterations in oral glucose tolerance due to adrenergic blockers, beyond their effects on glucose absorption, can be, to a large extent, mediated by their effects on insulin and glucagon secretion reflecting both hepatic and peripheral glucose metabolism.